Project Summary The efficacy of a drug depends directly on its method of delivery, which influences all aspects of its pharmacokinetic properties. Biopharmaceuticals, including protein drugs (e.g., insulin, human growth factor) and antibody drug conjugates (ADCs), offer tremendous promise for an increasingly broad portfolio of treatments, but they are highly susceptible to deactivation during formulation and delivery. Among the most promising strategies for the delivery of protein drugs is affinity controlled release (ACR), which allows for the formulation of protein drugs in neutral aqueous environments and largely preserves protein structure and function. ACR uses the selective interaction of a drug with its binding partner immobilized on a polymer matrix to prolong drug release. The rate of release depends directly on the binding affinity of the complex. Binding partners for a given protein, however, are often not available, and tailoring the binding properties to a desired application requires challenging development work. The proposed research seeks to gain full control of the rate of drug release using the extraordinary properties of the synthetic host cucurbit[7]uril (Q7). Q7 binds organic guests in aqueous solution with Kd values ranging from millimolar to attomolar. This unique ability to program the binding affinity will enable two aims, specifically the control of drug release from a hydrogel by conjugating the drug to a guest of desired affinity and modifying the hydrogel with Q7, and by introducing competitive binders to control the binding affinity. If successful, the proposed research will yield novel and general solutions to the problem of controlling the sustained release of protein drugs from compatible matrices. It will generate 5-6 publications with undergraduate coauthors and considerably elevate the biomedical research culture at Trinity University.